The bacterial microbiome modulates the initiation of brain metastasis by impacting the gut-to-brain axis.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE286123 | GEO | 2025/01/09
REPOSITORIES: GEO
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Project description:Brain metastasis (BrM) represents a challenging clinical issue. The most common treatment options are surgery and irradiation. Little is known about the complex cellular and molecular microenvironment of BrM, thus lacking molecular targets to combat this dismal disease. It is known that macrophages from the periphery (monocyte-derived macrophages, MDM) and microglia, the brain-resident macrophages, comprise the most abundant stromal cell types in BrM. However, it is not known if both cell types represent a homogeneous cell population with redundant functions or if there are differences due to their ontologic origin. Besides breast cancer and melanoma, the highest incidence of BrM can be found in lung cancer. To gain deeper insight into the myeloid immune landscape, we here provide a resource for the transcriptional landscape of distinct myeloid immune cells associated with lung-to-brain metastasis. Microglia, MDMs, inflammatory monocytes, and granulocytes were FACS-purified from lung-to-brain metastasis at distinct stages following tumor onset and during BrM progression. To evaluate molecular changes due to application of standard therapy, these 4 cell types were also purified at distinct time points upon whole brain radiotherapy of tumor-bearing mice. Additionally, microglia of irradiated mice without BrM were analyzed. Together, our RNA Seq data provide a framework for the identification of molecular targets of the myeloid immune cell landscape in lung cancer BrMs.
2020-05-13 | GSE137762 | GEO
Project description:Brain metastases (BrMs) are the leading cause of death in patients with solid cancers. BrMs exhibit a highly immunosuppressive milieu and poor response to immunotherapies; however, the underlying mechanism remains largely unclear. Here, we show that upregulation of HSP47 in tumor cells drives metastatic colonization and outgrowth in brain by creating an immunosuppressive microenvironment. HSP47-mediated collagen deposition in the metastatic niche promotes microglial polarization to M2 phenotype via the α2β1 integrin/NF-κB pathway, which upregulates the anti-inflammatory cytokines and represses CD8+ T cell anti-tumor responses. Depletion of microglia reverses HSP47-induced inactivation of CD8+ T cells and abolishes brain metastasis. Col003, an inhibitor disrupting HSP47-collagen association restores an anti-tumor immunity and enhances the efficacy of anti-PD-L1 immunotherapy in BrMs-bearing mice. Our study supports that HSP47 is a critical determinant of M2 microglial polarization and immunosuppression, and blocking the HSP47-collagen axis represents a promising therapeutic strategy against brain metastatic tumors.
2024-03-22 | GSE261941 | GEO
Project description:Background: The long-term high-fat, high-sugar diet exacerbates type 2 diabetes mellitus (T2DM)-related cognitive impairments. The negative impact of poor dietary patterns on brain development and neurological function may be related to gut microbiota disturbance. The role of phlorizin in mitigating glucose and lipid metabolism disorders is well documented. However, the protective effect of phlorizin on diabetes-related cognitive dysfunction is unclear. Therefore, the present study aimed to investigate the effect of dietary supplementation of phlorizin on high-fat and high-fructose diet (HFFD)-induced cognitive dysfunction and evaluate the crucial role of the microbiota-gut-brain axis. Results: Dietary supplementation of phlorizin for 14 weeks effectively prevented glucolipid metabolism disorder, spatial learning impairment, and memory impairment in HFFD mice. In addition, phlorizin improved the HFFD-induced decrease in synaptic plasticity, neuroinflammation, and excessive activation of microglia in the hippocampus. Transcriptomics analysis shows that the protective effect of phlorizin on cognitive impairment was associated with increased expression of neurotransmitters and synapse-related genes in the hippocampus. Phlorizin treatment alleviated colon microbiota disturbance, mainly manifested by an increase in gut microbiota diversity and the abundance of short-chain fatty acid (SCFA)-producing bacteria. The level of microbial metabolites, including SCFA, inosine 5'-monophosphate (IMP), and D (-)-beta-hydroxybutyric acid (BHB) were also significantly increased after phlorizin treatment. Moreover, integrating multiomics analysis observed tight connections between phlorizin-regulated genes, microbiota, and metabolites. Furthermore, removal of the gut microbiota via antibiotics treatment diminished the protective effect of phlorizin against HFFD-induced cognitive impairment, underscoring the critical role of the gut microbiota in mediating cognitive behavior. Importantly, supplementation with SCFA and BHB alone mimicked the regulatory effects of phlorizin on cognitive function. Conclusions: These results indicate that gut microbiota and their metabolites mediate the ameliorative effect of phlorizin on HFFD-induced cognitive impairment. Therefore, phlorizin can be used as an easy-to-implement nutritional therapy to prevent and alleviate metabolism-related neurodegenerative diseases by targeting the regulation of the microbiome-gut-brain axis.
2024-03-20 | GSE261887 | GEO
Project description:Antibiotics have long-lasting consequences on the gut microbiota with the potential to impact host physiology and health. However, little is known about the transgenerational impact of an antibiotic-perturbed microbiota. Here we demonstrated that adult pregnant female mice inoculated with a gut microbial community shaped by antibiotic exposure passed on their dysbiotic microbiota to their offspring. This dysbiotic microbiota remained distinct from controls for at least 5 months in the offspring without any continued exposure to antibiotics. By using IL-10 deficient mice, which are genetically susceptible to colitis, we showed mice that received an antibiotic-perturbed gut microbiota from their mothers had increased risk of colitis. Taken together, our findings indicate that the consequences of antibiotic exposure affecting the gut microbiota can extend to a second generation.
2017-12-01 | GSE92623 | GEO
Project description:Here we present an integrative analysis of 15 human parenchymal BrMs as a resource, generated by single-cell transcriptomics, and complemented with two mouse models- and in silico- approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and reveal stromal immunosuppressive states, enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a novel framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental- traits.
2021-11-12 | GSE186344 | GEO
Project description:Gut-brain connections monitor the intestinal tissue and its microbial and dietary content1, regulating both intestinal physiological functions such as nutrient absorption and motility2,3, and brain–wired feeding behaviour2. It is therefore plausible that circuits exist to detect gut microbes and relay this information to central nervous system (CNS) areas that, in turn, regulate gut physiology4. We characterized the influence of the microbiota on enteric–associated neurons (EAN) by combining gnotobiotic mouse models with transcriptomics, circuit–tracing methods, and functional manipulation. We found that the gut microbiome modulates gut–extrinsic sympathetic neurons; while microbiota depletion led to increased cFos expression, colonization of germ-free mice with short-chain fatty acid–producing bacteria suppressed cFos expression in the gut sympathetic ganglia. Chemogenetic manipulations, translational profiling, and anterograde tracing identified a subset of distal intestine-projecting vagal neurons positioned to play an afferent role in microbiota–mediated modulation of gut sympathetic neurons. Retrograde polysynaptic neuronal tracing from the intestinal wall identified brainstem sensory nuclei activated during microbial depletion, as well as efferent sympathetic premotor glutamatergic neurons that regulate gastrointestinal transit. These results reveal microbiota–dependent control of gut extrinsic sympathetic activation through a gut-brain circuit.
2020-03-20 | GSE145986 | GEO
Project description:“Dysbiosis" of the maternal gut microbiome, in response to environmental challenges such as infection, altered diet and stress during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior. However, whether the maternal gut microbiome regulates neurodevelopment in the absence of environmental challenge remains unclear. In addition, whether the maternal microbiome exerts such influences during critical periods of embryonic brain development is poorly understood. Here we investigate how depletion, and selective reconstitution, of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibit widespread transcriptomic alterations in the fetal brain relative to conventionally-colonized controls, with reduced expression of several genes involved in axonogenesis. In addition, embryos from microbiome-depleted mothers exhibit deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic guidance cues and growth factors. Consistent with the importance of fetal thalamocortical axonogenesis for shaping neural circuits for sensory processing, restricted depletion of the maternal microbiome from pre-conception through mid-gestation yields offspring that exhibit tactile hyposensitivity in select sensorimotor behavioral tasks. Gnotobiotic colonization of antibiotic-treated dams with a limited consortium of spore-forming bacteria indigenous to the gut microbiome prevents abnormalities in fetal brain gene expression, fetal thalamocortical axonogenesis and adult tactile sensory behavior associated with maternal microbiome depletion. Metabolomic profiling reveals that the maternal microbiota regulates levels of numerous small molecules in the maternal serum as well as the brains of fetal offspring. Select microbiota-dependent metabolites – trimethylamine N-oxide, 5-aminovalerate, imidazole propionate, and hippurate – sufficiently promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites during early gestation abrogates deficiencies in fetal thalamocortical axons and prevents abnormalities in tactile sensory behavior in offspring from microbiome-depleted dams. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis and select tactile sensory behaviors in mice, likely by signaling of microbially modulated metabolites to neurons in the developing brain.
2020-04-17 | GSE147183 | GEO
Project description:Purpose: Gut microbiota-brain axis serves as an emerging pathway affecting brain function. Hindgut has a higher proportion of microbes than foregut, however whether alteration in hindgut microbiota is related to brain functional change remains unclear. The present study used antibiotics to modulate the hindgut microbiota, to investigate the changes in the functions of porcine hypothalamus. Methods: Twelve piglets (12.08 ± 0.28 kg) fitted with T-cannula at the distal ileum were fed a standard diet and randomly assigned to two groups (n=6) for ileal infusions of saline (control group) and an antibiotic mix (ampicillin, gentamycin and metronidazole; antibiotic group), respectively. After the 25-day experiment, the microbiota and metabolites in feces, concentrations of amino acids and neurotransmitters in hypothalamus and blood, and transcriptomics profiles of hypothalamus were analyzed. Results: The results showed that the antibiotic infusion resulted in an increase in aromatic amino acids (AAA)-utilizing genera, notably Lactobacillus, and a decrease in the concentrations of AAAs including tryptophan, tyrosine and phenylalanine in feces. Correspondingly, concentrations of AAAs in the blood and hypothalamus also decreased. In the hypothalamus, the concentrations of AAAs related neurotransmitters 5-HT and dopamine decreased. Meanwhile, the compensatory upregulations of neurotransmitter transporter genes such as SERT, DAT and synthesis-related genes TPH2 and AADC were observed (adjusted P < 0.001). Furthermore, the concentrations of 5-HT and dopamine decreased in the blood. Conclusion: In conclusion, the results revealed that the ileal antibiotic infusion could affect the expressions of neurotransmitters in the porcine hypothalamus. The changes of hindgut microbial composition, circulating AAA profile and hypothalamic neurotransmitter expressions indirectly suggested that the hindgut microbiota may affect the brain functions.
2018-12-20 | GSE97738 | GEO
Project description:Brain metastases (BrMs) are a devastating complication of solid tumors with challenging clinical management. In this study, immunogenomic and digital spatial analyses were applied to interrogate the peripheral blood and tumor specimens derived from 53 unique patients with metastatic brain tumors originating from different solid tumors including melanoma, breast cancer, lung cancer and renal cell carcinoma. In the peripheral blood, lower levels of neutrophil -lymphocytes ratio (NLR) were detected at time of craniotomy in patients with melanoma-derived brain metastasis (MBM) vs. non-melanoma- derived brain metastasis (non-MBM). Independently from the primary tumor of derivation, patients with BrMs and increased NLR levels were characterized by shorter overall survival (OS) following craniotomy. In the tumor microenvironment (TME), molecular evaluations performed on FFPEs revealed higher expression of genes and mRNA signatures identifying NK cells, CD8 cells and B cells in MBM (n=13) vs. non-MBM brain metastasis (n=41). Focusing on CD8 cells, higher infiltration of CD8+ cells were observed in patients with MBM with longer OS following craniotomy. Spatial proteomic analysis further highlighted the infiltration of CD8+ cells, antigen presenting cells- (HLA-DR+, CD11c+, B2M+), agonists of T cell activity (CD137+, CD40+) and B cells (CD20+) enriched in MBM vs non-MBM. On the contrary, an increased expression of genes associated with neuro-development, cell- cell adhesion, neutrophil enrichment together with the increased infiltrations of cells promoting neuro-differentiation (Neun+, S100+), immune regulatory functions (CD25+, CD127+), and granulocytes aggregation (CD66b+) were observed in non-MBM vs. MBM. These findings highlight that the TME of BrMs plays a pivotal role in the pathogenesis and therapeutic resistance of BrMs derived from different solid tumors. Our results also suggest that distinct neuro-immune interplay may contribute to treatment resistance in BrMs.
2024-09-11 | GSE245467 | GEO
Project description:This project analysis brain proteome of honeybee (Apis mellifera). We aim to find out how gut microbiota affect brain functions.
2020-11-02 | PXD022304 |